DESCRIPTION (Investigator's abstract): Autosomal dominant leukodystrophy (ADLD) is a rare adult-onset demyelinating disorder. We have identified 6 families with this disorder. Two of these are large pedigrees for whom a tremendous amount of clinical, neuroradiological and neuropathological data has been collected. Although these patients share many clinical features with other white matter disorders, unique neuropathological findings suggest that the genesis of this disorder neither resides in defects of structural myelin proteins nor fatty acid metabolism in peroxisomes. ADLD is not an immune disease like multiple sclerosis (MS). We've demonstrated that lesions in ADLD brain have dramatic reduction in astrocyte number and that the surviving astrocytic cells are morphologically very abnormal. We hypothesize that ADLD results from a defect that interferes with a unique element in the myelination process and that understanding of this defect may provide novel insights into the process of myelin maintenance and turnover. We have localized the gene causing ADLD in these two large families to chromosome 5q3 1. Fine mapping has further narrowed the region and a complete physical map predicts the gene to reside within 3 megabases, much of which has already been sequenced. Candidate gene identification and testing are underway. Some genes in the region have already been eliminated using various mutation analysis strategies. Several plausible candidates are currently being tested including a novel gene with multiple EGF-like domains. This proposal outlines a strategy for identifying and characterizing the gene. Available patient material, physical mapping reagents and genomic sequence position us well for accomplishing this goal. In addition, experiments will be pursued toward preliminary characterization of both the wild-type and mutant ADLD protein. Understanding the cause of this demyelinating disorder may yield clues to genetic factors that modulate the expression of acquired leukodystrophies. Ultimately, discovery of a new element in the synthesis and maintenance of myelin may provide a novel target for compounds that may stimulate remyelination in more common disorders like MS.